Implantable medical devices, whether partially or completely implanted in the body, are frequently exposed to multiple types of physiological environments. It is frequently desirable for a device to exhibit different properties or biological functionality on different regions of the device surface depending on the physiological environment. Examples of specific functions that may be desirable for medical implant surfaces include:
Example 1—Cell Specific Adhesion and Attraction: It is frequently desirable to promote the adhesion of specific cells to surfaces. For example, for orthopedic implants and dental, it is desirable to specifically attract osteoblasts to a surface. For devices in contact with arterial walls, such as stents, it may be desirable to promote adhesion of specific endothelial cells to the outer wall of the stent to promote the arterial wall to heal and incorporate the stent.
Example 2—Non-Adhesion: It is frequently desirable to prevent adhesion of cells, proteins or other biomolecules to certain surfaces of medical implants. For example, implant surfaces with long term exposure to blood may generate thrombus. Inflammatory cells may also adhere to and proliferate on implant surfaces leading to increased inflammation and decreased healing rates. Adherence of thrombus and inflammatory cells can be minimized by a non-adherent surface.
Example 3—Anti-Corrosion: When exposed to physiological conditions, the surface of a metal implant corrodes and leaches metal ions into the body. Some patients exhibit heightened sensitivity or allergic response to certain metal alloys. For example, some patients exhibit nickel sensitivity. Metal sensitivity may lead to implant rejection and require explantation. Other metal ions, such as chromium, may have long term toxicity. It would be desirable to design a coated medical device that retains its medical functionality, but that exhibits significantly lower leaching of metal ions.
Example 4—Anti-infection: Infection presents a serious concern for implants. It would be desirable to covalently attach antibiotics, anti-microbial agents or agents that disrupt microbial pathogenesis such as anti-quorum sensing agents to regions of an implant.
Example 5—Anti-inflammatory: Implantation or deployment of medical devices frequently causes injury at the site of deployment/implantation. For example, balloon expandable stents injure the arterial wall when deployed resulting in inflammation that causes partial or complete restenosis of the artery. Similarly with orthopedic implants, trauma and inflammation from implantation results in long healing times. It would be desirable to provide an anti-inflammatory coating on portions of an implant.
Creating a stable bond between bone tissue and the surface of metallic bone implants is a research topic of considerable interest. Poor bonding with the interface between the metallic surface of the implant and the bone tissue leads to low mechanical strength of the bone-to-implant junction and the possibility of subsequent implant failure.
Titanium and titanium alloys are used extensively as dental and orthopedic implants. Currently, there is no effective way to obtain strong attachment of incipient bone with the implant material at the interface between the surfaces of the two materials in order to “stabilize” the implant.
An important goal for interface optimization is to use species which are biocompatible and which enable bone mineralization at the interface following implantation. Bone tissue is a combination of protein and mineral content, with the mineral content being in the form of hydroxyapatite.
The problem of interface synthesis is often approached from the prospective of high temperature methods, including using plasma or laser-induced coating techniques. However, these methods engender problems of implant heating and surface coverage. For example, calcium phosphate deposition at high temperatures can give rise to ion migration. Plasma-induced phosphate coating of a titanium substrate gives surface hydroxyapatite as well as surface calcium phosphate, titanates and zirconates. Therefore, control of surface stoichiometry can be problematic, and defects at the interface may translate into poor mechanical strength.
The use of intermediate layers, for example of zirconium dioxide, to enhance hydroxyapatite adhesion and interface mechanical strength has been explored with success. However, a practical limitation involving laser or plasma deposition is that it is hard to obtain comprehensive coverage on a titanium implant of complex 3-dimensional structure. The zirconium dioxide interface formed at high temperatures is of low surface area and maintains few, if any, reactive functional groups for further surface modification chemistry.
Solution-phase surface processing does not suffer from the practical limitations of surface coverage that can be attendant with plasma or laser-based deposition methods, and procedures involving formation of hydroxyapatite from solution, often using sol-gel type processing, have been accomplished. Elegant methodologies have been developed in which graded interfaces have been prepared, extending from the pure implant metal to the biomaterial at the outer extremity by way of silicates. However, while solution-based procedures are inexpensive and give rise to materials resistant to dissolution by bodily fluids, adhesion of the hydroxyapatite to the implant metal is less strong than is observed when deposition is accomplished by plasma spraying techniques.
The deficiency of these solution approaches may lie in the nature of the native oxide surface of titanium materials. Exposure of a clean surface of titanium materials to oxygen results in the spontaneous formation of surface titanium oxides (native oxide). The exact chemical stoichiometry and structure of these oxides varies from material to material, and with depth in the oxide layer, with environmental variables, and with the processing history of the material. The oxide layer may be stoichiometric, super-stoichiometric, or sub-stoichiometric with respect to TiO2, a stable oxide of titanium. Generally, the uppermost layer of the native oxides comprises some form of TiO2. It may be crystalline, but if crystalline, it is generally disordered. Typically, many different phases exist within the oxide layer between the metal and the ambient environment. Generally, the uppermost layer of oxide includes widely dispersed hydroxyl functional groups bonded to a titanium atom. The surface forms spontaneously by exposing the metal or alloy to the ambient environment, and is alternatively described as the “native oxide surface” of a titanium material.
As described in co-pending U.S. patent application Ser. No. 10/701,591, filed Nov. 4, 2003, Ser. No. 10/405,557, filed Apr. 1, 2003, and Ser. No. 10/179,743, filed Jun. 24, 2002, each of which is incorporated herein by reference in their entirety, and as described in U.S. Pat. No. 6,433,359 to Kelley et al., it is known that a phosphorous acid can be used to provide a layer on an oxide surface. For example, the use of phosphonic acid species on implantable materials has been disclosed by Descouts et al. (U.S. application Ser. No. 10/432,025), which is incorporated herein by reference in its entirety. But these phosphonic acid species fail to strongly adhere to the implant because they are not covalently bonded via heating. In addition, Descouts does not disclose the preparation of different surface treatments on the same implant.
The inventors have recognized the need for the provision of coated medical devices with different desirable surface properties and coatings which have an improved degree of organization and/or improved adhesion strength and/or which can be applied to surfaces over a large area, particularly when the coating is to be applied in a pattern.